Prothioconazole, developed by Bayer Corporation, is a novel thio-triazole fungicide (U.S. Pat. No. 5,789,430A). The prothioconazole compound has a structure of formula 1

Prothioconazole is a class of demethylation inhibitors (DMIs), which acts through inhibiting 14-demethylation of lanosterol as a precursor of sterol in fungi. Prothioconazole has not only good systemic action and excellent protection, treatment and eradication activities, but also durable efficacy. A variety of field efficacy trials have demonstrated that prothioconazole has good safety profile to crops and favorable effects on disease prevention and cure as well as significant increase in yield. Moreover, prothioconazole provides broader-spectrum fungicidal activities compared to triazoles as fungicides.
Currently, prothioconazole is mainly used for preventing and curing numerous diseases of cereal crops such as wheat, barley, oilseed rape, peanuts, rice, legume crops, etc. Prothioconazole shows excellent prevention and cure effects on almost all diseases of wheat and barley, for example powdery mildew, banded sclerotial blight, fusarium wilt, leaf spot, rust, stalk break, net blotch and Rhynchosporium secalis. Prothioconazole can also prevent and cure soil-borne diseases such as sclerotium diseases and folia diseases such as gray mold, black spot, brown patch, black shank and rust on oilseed rape and peanuts.
U.S. Pat. No. 8,188,129B2 discloses an optically active isomer of prothioconazole.
Strategy of producing prothioconazole can be classified into two categories according to the origin of the sulfur atom. The first strategy of producing prothioconazole is through reaction of hyroxytriazole compound 2 as a key intermediate with sulfur (U.S. Pat. No. 4,913,727). Sulfur is the thio source for prothioconazole in such reaction. In this method, a substitution reaction of a chloride 3 (U.S. Pat. No. 4,913,727) or an epoxide 4 (U.S. Pat. No. 5,146,001) as a starting material with a triazole 5 may give the key intermediate 2. This substitution reaction also produces a significant amount of regioisomer 6 which needs to be removed by purification, thereby resulting in a lower yield (51-53%). The key intermediate 2 may be prepared through a reaction of a chloroketone 7 as a raw material and triazole 5 followed by a reaction with Grignard reagent 10, however, this method suffers similarly from regioselectivity.

U.S. Pat. No. 5,789,430 discloses a method of preparing prothioconazole through a direct reaction of a compound 2 and sulfur. Such reaction is carried out in the presence of N-methyl pyrrolidone as a solvent at 200° C. for 44 hours to produce prothioconazole (20% yield). In U.S. Pat. No. 6,172,236, a higher yield (75%) is obtained through the reaction in DMF at 140-160° C. where air is introduced, however, the reaction yield is still not satisfactory.
U.S. Pat. No. 5,789,430 also discloses an improved method of producing prothioconazole through a reaction of compound 2 and sulfur. In this method, deprotonation of compound 2 in THF solvent using n-BuLi is carried out followed by a reaction with sulfur. As a result, the yield of prothioconazole is greatly increased (93% yield). However, such process requires anhydrous, oxygen-free and ultra-low temperature conditions and the related equipment, and requires more than two equivalents of highly hazardous n-BuLi reagent. Therefore, it is not suitable for industrial production due to high cost and safety concerns. In addition, chemical regioselectivity also becomes problematic in this process. For example, (1) lack of control in the deprotonation of key intermediate 2 using n-BuLi will lead to formation of regioisomeric impurity 11; and (2) if the regioisomer 6 is not completely separated and removed during the production of key intermediate 2, it will result in a regioisomer impurity 12. These highly challenging separation and purification not only produce a large amount of wastes, but also greatly increase the cost at the same time.
US2013005985 discloses a method of preparing prothioconazole through deprotonation of compound 2 using Grignard reagent such as i-PrMgCl instead of n-BuLi followed by sulfurization. This method solves the safety problem associated with using n-BuLi reagent. Such process, however, still requires anhydrous, oxygen-free and ultra-low temperature conditions and the related equipment, and requires more than two equivalents of Grignard reagent. In addition, the yield is greatly reduced (from 93% of using n-BuLi to 68%).
DE4030039 discloses another method of preparing intermediate 2. This method employs epoxide 4 as a starting material to produce the target compound 2 through hydrazinolysis followed by a reaction with formamidine acetate. Such method successfully solves the regioselectivity problem in the above preparation of compound 2 through substitution with triazole 5, but the total yield is not desirable (64%).

U.S. Pat. No. 6,720,428 discloses a method of preparing intermediate 2 through a reaction of a compound 13 and N-dichloromethylformamidine chloride 14. This method has a very good triazole cyclization yield (99.6%), but N-dichloromethylformamidine chloride 14 needs to be prepared starting from the highly toxic HCN.
The second strategy of producing prothioconazole is through the use of thiocyanate as a sulfur atom contributor for prothioconazole molecule. U.S. Pat. No. 6,262,276 discloses a method where a thiosemicarbazide intermediate 16 is synthesized through a reaction of hydroxyhydrazine 15 and a thiocyanate such as ammonium thiocyanate and then the intermediate 16 is used to produce prothioconazole. This method solves to a great extent the problems associated with the first strategy of preparing prothioconazole, but this method still suffers from the problem of its own chemical regioselectivity during the production of thiosemicarbazide intermediate 16 (the purity of the product 16 is only 65.9%). Regioisomeric impurity 17 needs to be strictly controlled, otherwise in the next step reaction formation of isomeric impurity 11 will result.

U.S. Pat. No. 6,271,389 discloses a method of preparing prothioconazole through a reaction of hydroxyhydrazine 15 and a thiocyanate such as potassium thiocyanate in the presence of alkyl (aryl) aldehyde or ketone to produce intermediate 18 followed by a reaction with HCOOH/HCOOBu-i. As compared to the method disclosed in U.S. Pat. No. 6,262,276, the yield during production of intermediate 18 (U.S. Pat. No. 6,271,389) is increased to some degree (82%), but a deprotection is required in the next step, resulting in a yield decrease of greater than 10%. In addition, this method cannot eliminate the problem of formation of the regioisomeric impurity 19 completely.

U.S. Pat. No. 6,201,128 discloses another method of synthesizing prothioconazole using hydroxyhydrazine 15 as a starting material. Such method employs formaldehyde instead of alkyl (aryl) aldehyde or ketone (U.S. Pat. No. 6,271,389) to prepare an intermediate 20 followed by an oxidative dehydrogenation of intermediate 20 to produce prothioconazole. This method has an advantage of atom efficiency in the last step of reaction as compared to the method described in U.S. Pat. No. 6,271,389. The alkyl (aryl) aldehyde or ketone in U.S. Pat. No. 6,271,389 only acts as a protecting group, while the formaldehyde in U.S. Pat. No. 6,201,128 becomes part of the molecule of prothioconazole. However, compared to the intermediate 18 in U.S. Pat. No. 627,189, the intermediate 20 in U.S. Pat. No. 6,201,128 is relatively unstable due to less steric-hindrance because of the lack of two methyl groups. Additionally, since the formaldehyde is more active than acetone, the active protons in intermediate 20 tend to react readily with the formaldehyde to give polymeric byproducts. Moreover, this method does not completely eliminate the problem of formation of the regioisomeric impurity 21.

U.S. Pat. No. 6,559,317 discloses a method of preparing prothioconazole via FeCl3 mediated intermediate 20. Although the yield of the oxidation reaction is improved to some degree, the treatment of iron-containing wastes is an environmental problem.